Cannabinoids encompass a class of endogenous and exogenous compounds that have demonstrated analgesic properties in a number of nociceptive systems. Recent work has identified the endocannabinoid anandamide as an agonist at CB1/CB2 receptors, and at the vanilloid TRPV1 receptor where it can sensitize and desensitize ion channel activity. The mechanism(s) by which cannabinoids mediate TRPV1 receptors have been largely uncharacterized, thus it is important to investigate this phenomenon. In this proposal we will study the desensitization of TRPV1 receptors by cannabinoids through pharmacological, biochemical, and molecular techniques, bridging the gap between basic and clinical research. We will characterize receptor dephosphorylation on TRPV1 desensitization following cannabinoid treatments, determine the role of the phosphatase calcineurin in the cannabinoid signaling pathway responsible for TRPV1 desensitization, and investigate the use of cannabinoids in reducing sensitized TRPV1 activity in patients diagnosed with inflammatory pulpal necrosis. Results from these studies will provide evidence supporting the use of cannabinoids as a possible treatment for patients suffering from local inflammatory pain.